Defining the transcriptomic and epigenetic blueprint of anti-viral T cell memory and the role of novel transcription factors in memory generation

抗病毒CD 8 + T细胞构成免疫系统的关键臂，其对抗病毒感染并介导病原体从体内清除。慢性病毒感染如成年小鼠的持续性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染，以及人的B肝炎病毒（HBV）、丙型肝炎病毒（HCV）和人免疫缺陷病毒（HIV）感染诱导慢性炎性病症，其最终随着时间耗尽适应性宿主免疫系统，特别是CD 8 + T细胞。相比之下，疱疹病毒如巨细胞病毒（CMV）以无活性的潜伏形式持续存在并共存于宿主中，不会引起广泛的免疫失调。与其他病毒感染不同，CMV感染的控制在很大程度上取决于被称为膨胀性T细胞的独特的终末分化病毒特异性效应CD 8 + T细胞群体的积累，目前对其了解甚少。慢性病毒感染是人类面临的主要临床挑战，目前尚不清楚为什么不同的慢性感染会导致免疫控制策略中完全相反的T细胞反应。虽然已经描述了T细胞分化的几个方面，但定义记忆T细胞形成的关键属性和该过程的通用转录蓝图一直是一个主要挑战。将研究小鼠模型中慢性LCMV和CMV感染后的CD 8 + T细胞应答。将使用最先进的基因组技术评估病毒感染后产生的记忆CD 8 + T细胞的转录和表观遗传特征。将使用贝尔茨实验室中可用的独特报告小鼠品系来定义病毒感染后早期出现的干细胞样T细胞的时间动态。缺乏转录因子的小鼠品系（Irf 4-/-和Tox-/-Tox 2-/-小鼠模型）将用于了解这些TF在T细胞对慢性病毒感染应答中的作用。此外，该项目的一个主要目标是描绘有助于长期保护性免疫的T细胞的核心细胞和分子蓝图，并了解不同途径是如何产生的。为了提供对这些程序和途径的综合理解，将比较不同慢性病毒感染后产生的幼稚干细胞样抗肿瘤T细胞和记忆CD 8 + T细胞的转录和表观遗传特征。这将提供长期记忆T细胞的综合概况，在慢性环境中驱动保护。这种方法将导致发育转录蓝图，其中即使在免疫失调的阴影下，也会产生稳定和保护性的CD 8 + T细胞记忆。生物信息学分析的重点是识别CD 8 + T细胞记忆机制的独特组成部分，以及识别在多种环境中保守的统一核心程序，如不同的病毒感染和抗肿瘤反应。

Antiviral CD8+ T cells constitute a critical arm of immune system that fight virus infections and mediate pathogen clearance from the body. Chronic virus infections such as persistent lymphocytic choriomeningitis virus (LCMV) infection of adult mice, and hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections of humans induce chronic inflammatory conditions that ultimately exhaust the adaptive host immune system over time, in particular the CD8+ T cell. In contrast, herpesviruses such as cytomegalovirus (CMV) persist and coexist in the host in an inactive latent form and do not cause widespread immune dysregulation. Control of CMV infection, distinct from other virus infections, depends largely on the accumulation of a unique population of terminally-differentiated virus-specific effector CD8＋ T cells known as inflationary T cells, which currently are only poorly understood. Chronic virus infections constitute a major clinical challenge to humanity, and it remains unclear why different chronic infections result in diametrically opposing T cell responses in immune control strategies. Although several aspects of T cell differentiation have been described, defining key attributes of memory T cell formation and a universal transcriptional blueprint of this process has been a major challenge.CD8+ T cell responses following chronic LCMV and CMV infection in the mouse model will be studied. The transcriptional and epigenetic profile of the memory CD8+ T cells generated following virus infection will be assessed using state-of-the-art genomic technologies. The temporal dynamics of stem-cell like T cells that emerge early upon virus infection will be defined using unique reporter mouse strains available in Belz laboratory. Mouse strains that lack transcription factors (Irf4-/- and Tox-/-Tox2-/- mouse models) will be used to understand the role of these TFs in T cell responses to chronic virus infections. Moreover, a major objective of this project is to delineate a core cellular and molecular blueprint of T cells that contribute to long-term protective immunity and understand how different pathways are generated. To provide an integrated understanding of these programs and pathways, the transcriptional and epigenetic profile of naïve, stem-cell like anti-tumor T cells and memory CD8+ T cells generated following different chronic virus infections will be compared. This will provide an integrated profile of long-term memory T cells that drive protection in the chronic setting. This approach will lead to the developmental transcriptional blueprint in which stable and protective CD8+ T cells memory is generated, even in shadow of immune dysregulation. The bioinformatics analysis will be focused on identifying unique components of CD8+ T cell memory machinery, as well as, identifying a unified core program that is conserved in multiple settings such as different virus infections and anti-tumor responses.